Mono- and diepoxide derivatives of 23-deoxyl-LL-F28249 compounds

ABSTRACT

The present invention relates to novel derivatives of LL-F28249 compounds wherein the 23-hydroxyl group is replaced with hydrogen and the double bond at the C(26,27)-position is epoxidized concomitant with or without epoxidation of the double bond at the C(14,15)-position. The LL-F28249 compounds (collectively) are isolates from the fermentation broth of Streptomyces cyaneogriseus subspecies noncyanogenus having deposit accession number NRRL 15773. The compounds of the present invention are derived by regioselective epoxidation of 5,23-O,O-bissilylated LL-F28249 compounds at low temperature, desilylation, re-silylation of the 5-hydroxyl group, thiocarbonylation of the 23-hydroxyl group, disilyation followed by tributyltin hydride reduction. The novel deoxy compounds of the present invention have anthelmintic, insecticidal, ectoparasiticidal, nematicidal and acaricidal activity. Compositions containing these described derivatives as active ingredients thereof are described herein.

BACKGROUND OF THE INVENTION

The present invention relates to novel mono- and diepoxide derivativesof 23-deoxy LL-F28249 compounds. The term LL-F28249 is used to describecompounds produced by the fermentation broth of Streptomycescyaneogriseus subspecies noncyanogenus deposited in the NRRL underdeposit accession No. 15773. The morphological characteristics,compounds and method for their production are disclosed in EuropeanPatent Application No. 170,006, incorporated herein by referencethereto.

The LL-F28249 compounds are complex macrolids which have 5 olefinicbonds. The regioselective epoxidation of the C(26,27)-olefinic bondconcomitant with or without epoxidation of the C(14,15)-olefinic bond,followed by replacing the hydroxyl group at the 23-position withhydrogen is the subject of the present invention. These mono- anddiepoxy-23-deoxy-LL-F28249 compounds are useful for the prevention,treatment or control of helmintic, ectoparasitic, insect, acarid, andnematode infections and infestations in warm-blooded animals andagricultural crops.

SUMMARY OF THE INVENTION

The present invention provides novel C(26,27)epoxide andC(14,15;26,27)-diepoxide-23-deoxy derivatives of the compoundsdesignated LL-F28249α, β, ε, ζ, θ and ι.

The LL-F28249 compounds have the following structural formula:

    ______________________________________                                         ##STR1##                                                                     Component R.sub.1    R.sub.2 R.sub.3 R.sub.4                                  ______________________________________                                        LL-F28249α                                                                        CH(CH.sub.3).sub.2                                                                       H       CH.sub.3                                                                              CH.sub.3                                 LL-F28249β                                                                         CH.sub.3   H       CH.sub.3                                                                              CH.sub.3                                 LL-F28249ε                                                                      CH(CH.sub.3).sub.2                                                                       H       H       CH.sub.3                                 LL-F28249ζ                                                                         CH.sub.2 CH.sub.3                                                                        H       CH.sub.3                                                                              CH.sub.3                                 LL-F28249θ                                                                        CH(CH.sub.3).sub.2                                                                       H       CH.sub.3                                                                              CH.sub.2 CH.sub.3                        LL-F28249ι                                                                         CH(CH.sub.3).sub.2                                                                       H       CH.sub.2 CH.sub.3                                                                     CH.sub.3                                 ______________________________________                                    

The compounds of the present invention are useful anthelmintics,ectoparasiticides, insecticides, acaricides and nematicides in treating,preventing or controlling such diseases in warm-blooded animals, such aspoultry, cattle, sheep, swine, rabbits, horses, dogs, cats and humanbeings and agricultural crops.

Although these diseases have been recognized for years and therapiesexist for the treatment and prevention of the diseases, the presentinvention provides novel compounds in the search for more effectivetherapy useful in the treatment of said diseases. For instance, U.S.application for Letters Pat. Ser. Nos. 907,283, 907,188, 907,281,907,259, 907,187 and 907,284 of Asato and Asato et al., filed onSeptember 12, 1986 and incorporated herein by reference thereof providecompounds for such treatments. Also U.S. application for Letters Pat.Ser. Nos. 022849, 022850, 022906, 022848, and 022846 of Asato et al.,filed concurrently herewith and incorporated herein by reference thereofprovide compounds for such treatments.

U.S. Pat. No. 3,950,360, Aoki et al., April 13, 1976 discloses certainantibiotic substances obtained by culturing a Streptomycesmicroorganism, said compounds being useful as insecticides andacaricides. Further, an entire series of U.S. patents relates to certaincompounds produced by the fermentation of Streptomyces avermitilis (U.S.Pat. No. 4,171,314, Chabala et al., October 16, 1979; U.S. Pat. No.4,199,569, Chabala et al., April 22, 1980; U.S. Pat. No. 4,206,205,Mrozik et al., June 3, 1980; U.S. Pat. No. 4,310,519, Albers-Schonberg,January 12, 1982; U.S. Pat. No. 4,333,925, Buhs et al., June 8, 1982).U.S. Pat. No. 4,423,209, Mrozik, December 27, 1983 relates to theprocess of converting some of these less desirable components to morepreferred ones. Finally, British Patent Application No. 2166436 Adiscloses antibiotics also, as does Belgium Patent Application No.9041709A.

The present compounds or the pharmaceutically and pharmacologicallyacceptable salts thereof exhibit excellent and effective treatment,prevention and/or control of these serious diseases of warm-bloodedanimals.

It is an object of the present invention, therefore, to provide novelC(26,27)-epoxide and C(14,25;26,27)-diepoxide-23-deoxy derivatives ofLL-F28249α, β, ε, ζ, θ and ι. It is a further object of the presentinvention to provide a process for the preparation of these derivativesand to provide methods for preventing, treating or controlling endo- andectoparasitic (collectively parasitic), insect, nematode, and acaridinfections and infestations in warm-blooded animals and agriculturalcrops by providing compositions containing prophylactically,therapeutically, pharmaceutically or pesticidally effective amounts ofthe novel compounds. Another object of the invention is to providecompounds useful as intermediates for the preparation of novelantiparasitic and insecticidal compounds.

These and other objects of the invention will become apparent by themore detailed description of the invention provided hereinbelow.

DETAILED DESCRIPTION OF THE INVENTION

The LL-F28249 compounds which may act as precursors of the presentcompounds are represented by the following structural formula,

    ______________________________________                                         ##STR2##                                                                     Component R.sub.1    R.sub.2 R.sub.3 R.sub.4                                  ______________________________________                                        LL-F28249α                                                                        CH(CH.sub.3).sub.2                                                                       H       CH.sub.3                                                                              CH.sub.3                                 LL-F28249β                                                                         CH.sub.3   H       CH.sub.3                                                                              CH.sub.3                                 LL-F28249ε                                                                      CH(CH.sub.3).sub.2                                                                       H       H       CH.sub.3                                 LL-F28249ζ                                                                         CH.sub.2 CH.sub.3                                                                        H       CH.sub.3                                                                              CH.sub.3                                 LL-F28249θ                                                                        CH(CH.sub.3).sub.2                                                                       H       CH.sub.3                                                                              CH.sub.2 CH.sub.3                        LL-F28249ι                                                                         CH(CH.sub.3).sub.2                                                                       H       CH.sub.2 CH.sub.3                                                                     CH.sub.3                                 ______________________________________                                    

The compounds of the instant invention are represented by the followingstructural formula: ##STR3## wherein R₁ is methyl or isopropyl; R₂ ishydrogen, methyl or ethyl; and the dotted triangular figure with oxygenat C(14,15) indicates that either a double bond or an epoxide ispresent.

A preferred group of compounds of structure (I) includes R₁ asisopropyl; R₂ as methyl; and the dotted triangular figure with oxygen atC(14,15) indicating that either a double bond or an epoxide is present.

The most preferred compound of structure (I) include R₁ as isopropyl; R₂as methyl; and the dotted triangular figure with oxygen at C(14,15)indicating that a double bond is present.

The monoepoxide and diepoxide compounds of the present invention areprepared by treating the appropriately-protected LL-F28249 compound witha mild oxidizing agent at temperatures less than -20° C. The oxidizingagent useful in the present invention is capable of selectivelyoxidizing the C(26,27) double as well as the C(14,15) double bond, butnot other double bonds in the molecule. Selectivity also is attained bycontrolling the temperature of the oxidation in an inert solvent, suchas methylene chloride, chloroform and the like. Peroxide oxidizingagents, such as m-chloroperoxybenzoic acid, are representative of thepreferred oxidants in preparing the monoepoxy and diepoxy compounds ofthe present invention.

Generally, a slight excess of the oxidizing agent is employed, such as5%-20% excess, when it is desired to prepare the C(26,27) epoxide ingood yield. When epoxidation at the C(14,15) double bond also isdesired, an amount of oxidizing agent equivalent to a slight excess of 2moles is employed.

The epoxidation is generally conducted at temperatures less than -20° C.and -78° C. and is complete in 3-6 hours. Separation of the monoepoxideand the diepoxide is readily achieved by standard chromatographictechniques, such as column or preparative-plate chromatography.

The starting compounds of the present invention include theabove-mentioned LL-F28249 fermentation products. These compounds areinitially derivatized at the 5- and 23-hydroxy groups with atrisubstituted alkyl silyl group. One of the preferred protecting groupis t-butyldimethylsilyl group. The reaction is carried out by allowingthe LL-F28249 compound to react with at least two molar equivalents of asubstituted silyl halide, preferably a silyl chloride in an aproticsolvent such as dimethylformamide, methylene chloride or ethylenedichloride in the presence of imidazole and/or 4-dimethylaminopyridine.The reaction is completed in 2-8 hours at 50° C. to 80° C.

The silyl group is removed after epoxidation by stirring the silylderivative in methanol containing an acid, such as p-toluenesulfonicacid monohydrate or acetic acid. The reaction is complete in 1 to 8hours at 0° C. to 25° C., preferably at 0° C. to 10° C. Desilylationalso may be conducted in aqueous acetic acid at room temperature. Theaddition of a catalytic amount of FeCl₃ in the desilylation especiallyfacilitates the desilylation.

In preparing the compounds of the present invention, the 5-hydroxy groupis protected following the epoxidation. Suitable protecting groups aretrisubstituted silyl groups, such as t-butyldimethylsilyl andtrimethylsilyl, or trisubstituted silyloxyacetyl groups, such ast-butyldimethylsilyloxy acetyl group. The protecting groups, however,are not limited to these groups since other useful protecting groupssuch as acyl and substituted acyl, such as acetyl, trifluoroacetyl,chloroacetyl, trichloroacetyl, phenoxyacetyl and the like, also areuseful in the process of the present invention.

One of the preferred protecting groups is t-butyldimethylsilyl. Thisgroup is attached to the 5-hydroxyl group by reacting an unprotected5-hydroxy C(26,27)-epoxy- or C(14,15;26,27)-diepoxy-LL-F28249 compoundwith t-butyldimethylsilyl chloride in the presence of a base, such asimidazole, pyridine, 4-dimethylaminopyridine, triethylamine and thelike, in an aprotic solvent such as methylene chloride, toluene,ethylacetate, tetrahydrofuran, ethylenedichloride and the like. Thereaction is stirred at a temperature of about 0° C. to 30° C., and thereaction is complete in several hours, depending on the temperature ofthe reaction. The completion of the reaction is usually monitored byhigh performance liquid chromatography (HPLC) using reverse phase on aWhatman Partisil CCS/C₈ rapid analysis column.

Another preferred protecting group is t-butyldimethylsilyloxy acetylgroup. This group is attached to the 5-hydroxyl group by combining theunprotected C(26,27)-epoxy- or C(14,15;26,27)-diepoxy-LL-F28249 compoundin an aprotic solvent such as methylene chloride, toluene, ethylacetate, tetrahydrofuran, ethylenedichloride and the like, containing atertiary amine, such as pyridine or triethylamine, and adding theprotecting agent in the form of an acid halide. The reaction isconducted at a temperature of about 0° C. to 30° C. and is monitored byHPLC for completion.

For instance, the reaction of the present invention is carried out byallowing the C(26,27)-epoxy or C(14,15;26,27)-diepoxy-LL-F28249 compoundto react with a molar equivalent or slight excess of the trisubstitutedsilyl chloride in the presence of imidazole with or without a catalyticamount of 4-dimethylaminopyridine. The reaction is conducted in an inertsolvent, such as methylene chloride, ethylene dichloride ordimethylformamide at 15° C.-30° C. This protected epoxy or diepoxycompound is then reacted with O-(4-methylphenyl)chlorothiolformate inpyridine containing 4-dimethylaminopyridine at a temperatures of 25° C.to 50° C. The resulting 23-O[(4-methylphenoxy)thiocarbonyl] derivativeis desilylated with acid as described hereinabove and then is reduced inan inert solvent, such as refluxing toluene, under nitrogen atmospherewith tributyltin hydride/azobisisobutyronitrile until the reaction iscomplete. The reduced product is the mono- or diepoxide derivatives,23-deoxy-LL-F28249 compound.

The process is schematically shown in the following diagram: ##STR4##

The novel compounds of the present invention have significant activityas anthelmintics, ectoparasiticides, insecticides, nematicides andacaricides in human and animal health areas and in agriculture.

The disease or group of diseases described generally as helminthiasis isdue to infection of an animal host with parasitic worms known ashelminths. Helminthiasis is a prevalent and serious economic problem indomesticated animals such as swine, sheep, horses, cattle, goats, dogs,cats and poultry. Among the helminths, the group of worms described asnematodes causes widespread and often times serious infection in variousspecies of animals. The most common genera of nematodes infecting theanimals referred to above are Haemonchus, Trichostrongylus, Ostertagia,Nematodirus, Cooperia, Ascaris, Bunostomum, Oesophagostomum, Chabertia,Trichuris, Strongylus, Trichonema, Dictyocaulus, Capillaria, Heterakis,Toxocara, Ascaridia, Oxyuris, Ancylostoma, Uncinaria, Toxascaris andParascaris. Certain of these, such as Nematodirus, Cooperia, andOesophagostomum primarily attack the intestinal tract while others, suchas Haemonchus and Ostertagis, are most prevalent in the stomach. Stillothers such as Dictyocaulus are found in the lungs. Also, otherparasites may be located in other tissues and organs of the body such asthe heart and blood vessels, subcutaneous and lymphatic tissue and thelike. The parasitic infections known as helminthiases lead to anemia,malnutrition, weakness, weight loss, severe damage to the walls of theintestinal tract and other tissues and organs, and if left untreated,may result in death of the infected host. The mono- and diepoxides ofthe 23-deoxy-LL-F28249 derivatives of the LL-F28249 compounds of thepresent invention unexpectedly have high activity against theseparasites.

Additionally, they also are active against Dirofilaria in dogs,Nematospiroides, Syphacia, Aspiculuris in rodents, arthropodectoparasites such as ticks, mites, lice, fleas, blowfly of animals andbirds, the ectoparasite Lucilia sp. of sheep, biting insects andmigrating dipterous larvae such as Hypoderma sp. in cattle, Gastrophilusin horses and Cuterebra sp. in rodents.

The compounds of the present invention also are useful in treating,preventing or controlling parasites which infect human beings, as well.The most common genera of parasites of the gastrointestinal tract of manare Ancylostoma, Necator, Ascaris, Strongyloides, Trichinella,Capillaria, Trichuris, and Enterobius. Other medically important generaof parasites which are found in the blood or other tissues and organsoutside the gastrointestinal tract are the filiarial worms such asWuchereria, Brugia, Onchocerca and Loa, Dracunculus and extra-intestinalstages of the intestinal worms Strongyloides and Trichinella. Thepresent compounds also are of value against arthropods parasitizing man,biting insects and other dipterous pests causing annoyance to man.

These compounds are also active against household pests such as thecockroach, Blattella sp., clothes moth, Tineola sp., carpet beetle,Attagenus sp., and the housefly Musca domestica.

Insects pests of stored grains such as Tribolium sp., Tenebrio sp., andof agricultural plants such as spider mites (Tetranychus sp.), southernarmy worms, tobacco budworms, boll weevils, aphids (Acyrthiosiphon sp.),migratory orthopterans such as locusts and immature stages of insectsliving on plant tissues are controlled by the compounds of the presentinvention as well as soil nematodes and plant parasites such asMeloidogyne sp., which may be of importance in agriculture.

The compounds of the present invention may be administered orally orparenterally for animal and human usage, and may be formulated in liquidor solid form for agricultural use. Oral administration may take theform of a unit dosage from such as a capsule, bolus or tablet, or as aliquid drench where used as an anthelmintic for animals.

The animal drench is normally a solution, suspension or dispersion ofthe active compound, usually in water, together with a suspending agentsuch as bentonite and a wetting agent or like excipient. Generally, thedrenches also contain an antifoaming agent. Drench formulationsgenerally contain about 0.001% to 0.5%, by weight, of the activecompound. Preferred drench formulations contain about 0.01% to 0.1% byweight.

Capsules and boluses comprise the active ingredient admixed with acarrier vehicle such as starch, talc, magnesium stearate or di-calciumphosphate.

Where it is desired to administer these derivatives of LL-F28249 in adry, solid unit dosage form, capsules, boluses or tablets containing thedesired amount of active compound usually are employed. These dosageforms are prepared by intimately and uniformly mixing the activeingredient with suitable finely divided diluents, fillers,disintegrating agents and/or binders such as starch, lactose, talc,magnesium stearate, vegetable gums and the like. Such unit dosageformulations may be varied widely with respect to their total weight andcontent of the active compound depending upon factors such as the typeof infection and the weight of the host.

When the active compound is to be administered via an animal feedstuff,it is intimately dispersed in the feed or used as a top dressing or inthe form of pellets which may then be added to the finished feed oroptionally fed separately. Alternatively, the active compounds of thepresent invention may be administered to animals parenterally, such asby intraruminal, intramuscular, intratracheal, or subcutaneousinjection. In such an event, the active compound is dissolved ordispersed in a liquid carrier vehicle.

For parenteral administration, the active compound is suitably admixedwith an acceptable vehicle, preferably of the vegetable oil variety suchas peanut oil, cotton seed oil and the like. Other parenteral vehiclessuch as organic preparations using solketal, propylene glycol, glycerolformal, and aqueous parenteral formulation also are used. The active23-deoxy compound or compounds of the present invention are dissolved orsuspended in the parenteral formulation for administration. Suchformulations generally contain about 0.005%, by weight, of the activecompound.

Although the compounds of the present invention are primarily used inthe treatment, prevention or control of helminthiasis, they also areuseful in the prevention and treatment of diseases caused by otherparasites. For example, arthropod parasites such as ticks, lice, fleas,mites and other biting insects in domesticated animals and poultry arecontrolled by the present compounds. These compounds also are effectivein treatment of parasitic diseases that occur in other animals includinghuman beings. The optimum amount to be employed will, of course, dependupon the particular compound employed, the species of animal to betreated and the type and severity of parasitic infection or infestation.Generally, the amount useful in oral administration of these novelcompounds is about 0.001 mg to 10 mg per kg of animal body weight, suchtotal dose being given at one time or in divided doses over a relativelyshort period of time (1-5 days). The preferred compounds of theinvention give excellent control of such parasites in animals byadministering about 0.025 mg to 3 mg per kg of animal body weight in asingle dose. Repeat treatments are given as required to combatre-infections and are dependent upon the species of parasite and thehusbandry techniques being employed. The techniques for administeringthese materials to animals are known to those skilled in the veterinaryfield.

When the compounds described herein are administered as a component ofthe animal's feed, or dissolved or suspended in the drinking water,compositions are provided in which the active compound or compounds areintimately dispersed in an inert carrier or diluent. An inert carrier isone that will not react with the active component and that will beadministered safely to animals. Preferably, a carrier for feedadministration is one that is, or may be, an ingredient of the animalration.

Suitable compositions include feed premixes or supplements in which theactive compound is present in relatively large amounts, wherein saidfeed premixes or supplements are suitable for direct feeding to theanimal or for addition to the feed either directly or after anintermediate dilution or blending step.

Typical carriers or diluents suitable for such compositions includedistillers' dried grains, corn meal, citrus meal, fermentation residues,ground oyster shells, wheat shorts, molasses solubles, corn cob meal,edible bean mill feed, soya grits, crushed limestone and the like. Theactive compounds are intimately dispersed throughout the carrier bymethods such as grinding, stirring, milling or tumbling. Compositionscontaining about 0.005% to 2.0%, by weight, of the active compound areparticularly suitable as feed premixes.

Feed supplements, which are fed directly to the animal, contain about0.0002% to 0.3%, by weight, of the active compounds. Such supplementsare added to the animal feed in an amount to give the finished feed theconcentration of active compound desired for the treatment, preventionand/or control of parasitic diseases. Although the desired concentrationof active compound will vary depending upon the factors previouslymentioned as well as upon the particular derivative employed, thecompounds of this invention are usually fed at concentrations of about0.00001% to 0.02% in the feed in order to achieve the desiredantiparasitic result.

The compounds also may be administered by pouring on the skin of animalsvia a solution. Generally, the active compounds are dissolved in asuitable inert solvent, such as dimethylsulfoxide, propylene glycol orthe like, alternatively in combination of solvents, for the pour-onadministration.

The compounds of this invention also are useful in combatingagricultural pests that inflict damage upon growing or stored crops. Thepresent compounds are applied, using known techniques such as sprays,dusts, emulsions and the like, to the growing or stored crops to effectprotection from such agricultural pests.

The present invention is illustrated by the following examples which areillustrative of said invention and not limitative thereof.

EXAMPLE 1 5,23-O,O-(Bis-tert-butyldimethylsilyl)-LL-F28249α

In 20 mL of dimethylformamide, 2.0 g of LL-F28249α, 3.72 g oft-butyldimethylsilyl chloride and 2.38 g of imidazole are heated at 60°C. in an oil bath under N₂ for 6 hours. The mixture is cooled, quenchedwith 5 mL of H₂ O, and diluted with 100 mL of H₂ O and 50 mL of brine.The product is then extracted from the aqueous mixture with 2×50 mL ofEt₂ O. The combined Et₂ O extracts are washed with 2×25 mL of H₂ O, 10mL of brine and dried over MgSO₄. Removal of Et₂ O affords the titlecompound which is identified by mass spectrometry and NMR spectroscopy.

EXAMPLES 2 AND 3 LL-F28249α-C(26,27)-Epoxide andLL-F28249α-C(14,15;26,27)-Diepoxide

In 5 mL of CH₂ Cl₂, 105.4 mg of5,23-O,O-(bis-t-butyldimethylsilyl)-LL-F28249α is dissolved, and thesolution is cooled in dry-ice/acetone bath while 27.8 mg ofm-chloroperoxybenzoic acid in 300 mL is added. After an hour of stirringunder N₂, the temperature is raised to -42° C. for 2 hours and -20° C.for an hour. The solution is washed with 1 mL of saturated Na₂ SO₃solution, 1 mL of saturated NaHCO₃ solution and 1 mL of brine. Afterdrying over Na₂ SO₄, the solution is evaporated and residue ischromatographed on silica gel in a flash-chromatography apparatus using5% EtOAc/hexane followed by 10% EtOAc/hexane. Fractions 16 to 20 afford45 mg of monoepoxide while fractions 31-36 affords 12.1 mg of diepoxide.

In 1 mL of MeOH, 30.3 mg of epoxide is stirred with 10.2 mg ofp-toluenesulfonic acid monohydrate for 7.5 hours under N₂. The mixtureis diluted with 1 mL of saturated NaHCO₃ solution and 5 mL of H₂ O andextracted with 3×2 mL of Et₂ O. The combined Et₂ O extracts are washedwith brine, dried over MgSO₄, filtered and evaporated to dryness. Theresidue is chromatographed on silica gel using 2% isopropanol/CH₂ Cl₂ ona flash-chromatography apparatus to afford 9.4 mg ofLL-F28249α-C(26,27)-epoxide, which is identified by mass spectrometryand NMR spectroscopy.

Similarly, the diepoxide is treated with p-toluenesulfonic acid toafford deblocked LL-F28249α-C(14,15;26,27)-diepoxide.

EXAMPLES 4-7 5,23-O,O-(Bis-tert-butyldimethylsilyl)-LL-F28249 compounds

Using the procedure of Example 1, the following bis-silylated productsare prepared:

    ______________________________________                                         ##STR5##                                                                            R.sub.1       R.sub.2                                                  ______________________________________                                               CH(CH.sub.3).sub.2                                                                          H                                                               CH.sub.2 CH.sub.3                                                                           CH.sub.3                                                        CH(CH.sub.3).sub.2                                                                          CH.sub.2 CH.sub.3                                               CH.sub.3      CH.sub.3                                                 ______________________________________                                    

EXAMPLES 8-15 LL-F28249-C(26,27)-epoxides andLL-F28249-C(14,15;26,27)-diepoxides

Using the method of Example 2, the following epoxides and diepoxides ofstructure (I) are prepared:

    ______________________________________                                         ##STR6##                      (I)                                                   R.sub.1       R.sub.2                                                  ______________________________________                                               CH(CH.sub.3).sub.2                                                                          H                                                               CH.sub.2 CH.sub.3                                                                           CH.sub.3                                                        CH(CH.sub.3).sub.2                                                                          CH.sub.2 CH.sub.3                                               CH.sub.3      CH.sub.3                                                 ______________________________________                                    

EXAMPLE 16 5-O-tert-Butyldimethylsilyl-LL-F28249α-C(26,27)-epoxide

In 5 mL of CH₂ Cl₂, 200 mg of LL-F28249α-C(26,27)-epoxide is treatedwith 130 mg of imidazole and then with 140 mg of t-butyldimethylsilylchloride (TBDMS chloride) in 5 mL of CH₂ Cl₂ under N₂ at roomtemperature. The reaction is stirred and monitored by high-performanceliquid chromatography (HPLC) for percent conversion. An additional 2.5equivalents of imidazole and TBDMS chloride are added, and stirring iscontinued for 5 days. The mixture is then washed with water (2×10 mL)and brine (20 mL), and the CH₂ Cl₂ solution is dried over MgSO₄. Thesolution is evaporated to dryness and the residue is chromatographedover silica gel using 1:1 heptane/CH₂ Cl₂ to afford the title compoundthat is identified by mass spectrometry and NMR spectroscopy.

EXAMPLES 17-20

Using the procedure of Example 16, the following silylated products areprepared:

    ______________________________________                                         ##STR7##                                                                            R.sub.1       R.sub.2                                                  ______________________________________                                               CH(CH.sub.3).sub.2                                                                          H                                                               CH.sub.2 CH.sub.3                                                                           CH.sub.3                                                        CH(CH.sub.3).sub.2                                                                          CH.sub.2 CH.sub.3                                               CH.sub.3      CH.sub.3                                                 ______________________________________                                    

EXAMPLES 21-25

Using the method of Example 16, the following silylated diepoxides ofstructure (I) are prepared:

    ______________________________________                                         ##STR8##                      (I)                                                   R.sub.1        R.sub.2                                                 ______________________________________                                               CH(CH.sub.3).sub.2                                                                           H                                                              CH.sub.2 CH.sub.3                                                                            CH.sub.3                                                       CH(CH.sub.3).sub.2                                                                           CH.sub.2 CH.sub.3                                              CH.sub.3       CH.sub.3                                                       CH(CH.sub.3).sub.2                                                                           CH.sub.3                                                ______________________________________                                    

EXAMPLE 2623-O[(4-methylphenoxy)thiocarbonyl]-LL-F28249α-C(26,27)-epoxide

In 2 mL of dry pyridine, 120 mg of5-O-tert-butyldimethylsilyl-LL-F28249α-C(26,27)-epoxide is stirred with4 mg of 4-dimethylaminopyridine under N₂ in an ice bath, and 0.24 mL ofO-p-tolyl chlorothiolformate is added via a syringe. The mixture isstirred at 3° C.-10° C. After 1 hour, 0.2 mL of O-p-tolylchlorothiolformate is added, and the mixture is stirred at 45° C. for anhour. The mixture is treated with 20 mL of iced H₂ O, stirred for 10minutes and extracted with 3×20 mL of Et₂ O. The combined ethereallayers are treated with HOAc and washed successively with H₂ O, NaHCO₃solution and brine. Evaporation of the ether affords the silylatedthiocarbonate compound, which is purified by chromatography andidentified by mass spectrometry and NMR spectroscopy. Desilylation isthen conducted by using the procedure of Example 2 to afford the titlecompound, that is identified by mass spectrometry and NMR spectroscopy.

EXAMPLES 27-30

Using the method of Example 26, the following thiocarbonyl derivativesare prepared:

    __________________________________________________________________________     ##STR9##                                                                             R.sub.1       R.sub.2                                                 __________________________________________________________________________            CH(CH.sub.3).sub.2                                                                          H                                                               CH.sub.2      CH.sub.3                                                        CH(CH.sub.3).sub.2                                                                          CH.sub.2 CH.sub.3                                               CH.sub.3      CH.sub.3                                                __________________________________________________________________________

EXAMPLES 31-35

Using the procedure of Example 26, the following thiocarbonatederivatives are prepared:

    __________________________________________________________________________     ##STR10##                                                                            R.sub.1       R.sub.2                                                 __________________________________________________________________________            CH(CH.sub.3).sub.2                                                                          H                                                               CH.sub.2 CH.sub.3                                                                           CH.sub.3                                                        CH(CH.sub.3).sub.2                                                                          CH.sub.2 CH.sub.3                                               CH.sub.3      CH.sub.3                                                        CH(CH.sub.3).sub.2                                                                          CH.sub.3                                                __________________________________________________________________________

EXAMPLE 36 23-Deoxy-LL-F28249α-C(26,27)-Epoxide

In 2 mL of toluene, 6.2 mg of23-O[(4-methylphenoxy)thiocarbonyl]-LL-F28249α-C(26,27)-epoxide iscombined with 3 microliters of tributyltin hydride and a catalyticamount of azobisisobutyronitrile and heated at reflux for 40 minutes.The toluene is removed in vacuo, and the residue is diluted with CH₂ Cl₂and chromatographed over silica gel using 2% EtOAc in CH₂ Cl₂. Theproduct is monitored by HPLC and evaporation of solvents affords thetitle compound, that is identified by mass spectrometry and NMRspectroscopy.

EXAMPLES 37-40

Using the procedure of Example 36, the following23-deoxy-LL-F28249-C(26,27)-epoxides are prepared from theircorresponding thiocarbonates listed in Examples 27-30:

    ______________________________________                                         ##STR11##                                                                           R.sub.1        R.sub.2                                                 ______________________________________                                               CH(CH.sub.3).sub.2                                                                           H                                                              CH.sub.2 CH.sub.3                                                                            CH.sub.3                                                       CH(CH.sub.3).sub.2                                                                           CH.sub.2 CH.sub.3                                              CH.sub.3       CH.sub.3                                                ______________________________________                                    

EXAMPLES 41-45

Using the procedure of Example 36, the following23-deoxy-LL-F28249-C(14,15;26,27)-diepoxides are prepared from theircorresponding thiocarbonates listed in Examples 31-35:

    ______________________________________                                         ##STR12##                                                                           R.sub.1        R.sub.2                                                 ______________________________________                                               CH(CH.sub.3).sub.2                                                                           H                                                              CH.sub.2 CH.sub.3                                                                            CH.sub.3                                                       CH(CH.sub.3).sub.2                                                                           CH.sub.2 CH.sub.3                                              CH.sub.3       CH.sub.3                                                       CH(CH.sub.3).sub.2                                                                           CH.sub.3                                                ______________________________________                                    

What is claimed is:
 1. A compound represented by structural formula (I):##STR13## wherein, R₁ is methyl or isopropyl; R₂ is hydrogen or ethyl;and the dotted triangular figure with oxygen at C(14,15) indicates thateither a double bond or an epoxide is present.
 2. A compound accordingto claim 1, wherein R₁ is isopropyl; R₂ is hydrogen or ethyl; and thedotted triangular figure with oxygen at C(14,15) indicates that either adouble bond or an epoxide is present.
 3. A compound according to claim2, wherein R₁ is isopropyl; R₂ is hydrogen or ethyl; and the dottedtriangular figure with oxygen at C(14,15) indicates that a double bondis present.
 4. A method for the prevention, treatment or control ofendoparasitic or ectoparasitic infections in warm-blooded animals, saidmethod comprising: orally, topically or parenterally administering to ananimal infected with endo- or ectoparasites, an endo-orectoparasiticidally effective amount of a compound represented bystructural formula (I), ##STR14## wherein said compound is R₁ as methylor isopropyl; R₂ as hydrogen or ethyl; and the dotted triangular figurewith oxygen at C(14,15) indicates that either a double bond or anepoxide is present.
 5. A method according to claim 4, wherein saidcompound is R₁ as isopropyl; R₂ as hydrogen or ethyl; and the dottedtriangular figure with oxygen at C(14,15) indicates that a double bondis present.
 6. A method for protecting crops, trees, shrubs, storedgrain and ornamentals from attack by insects, acarids and nematodes,said method comprising: applying to said crops, trees, shrubs, storedgrain and ornamentals or to the locus in which they are grown or storedan insecticidally-effective amount of a compound represented bystructural formula (I), ##STR15## wherein said compound is R₁ as methylor isopropyl; R₂ as hydrogen or ethyl; and the dotted triangular figurewith oxygen at C(14,15) indicates that a double bond or an epoxide ispresent.
 7. A method according to claim 6, wherein said compound is R₁as isopropyl; R₂ as methyl; and the dotted triangular figure with oxygenat C(14,15) indicates that a double bond is present.
 8. A method for thecontrol of plant nematodes, said method comprising: applying to thefoliage of plants, the soil in which they are grown or into the trunksthereof, a nematocidally-effective amount of a compound represented bystructural formula (I), ##STR16## wherein said compound is R₁ as methylor isopropyl; R₂ as hydrogen or ethyl; and the dotted triangular figurewith oxygen at C(14,15) indicates that either a double bond or anepoxide is present.
 9. A composition comprising: a prophylactically,therapeutically, pharmaceutically or insecticidally effective amount ofa compound represented by structural formula (I), ##STR17## wherein R₁is methyl or isopropyl; R₂ is hydrogen or ethyl; the dotted triangularfigure with oxygen at C(14,15) indicates that either a double bond or anepoxide is present; and an inert carrier; wherein said composition isused to control endo- or ectoparasitic pests which infect warm-bloodedanimals or to control insect, acarid and nematode pests which infestagricultural crops.